Fibroblast growth factor 2 lethally sensitizes cancer cells to stress-targeted therapeutic inhibitors

In malignant transformation, cellular stress-response pathways are dynami-cally mobilized to counterbalance oncogenic activity, keeping cancer cellsviable. Therapeutic disruption of this vulnerable homeostasis might changethe outcome of many human cancers, particularly those for which no effec-tive therapy is available. Here, we report the use of fibroblast growth factor2 (FGF2) to demonstrate that further mitogenic activation disrupts cellularhomeostasis and strongly sensitizes cancer cells to stress-targeted therapeu-tic inhibitors. We show that FGF2 enhanced replication and proteotoxicstresses in a K-Ras-driven murine cancer cell model, and combinations ofFGF2 and proteasome or DNA damage response-checkpoint inhibitorstriggered cell death. CRISPR/Cas9-mediated K-Ras depletion suppressedthe malignant phenotype and prevented these synergic toxicities in thesemurine cells. Moreover, in a panel of human Ewing’s sarcoma family tumorcells, sublethal concentrations of bortezomib (proteasome inhibitor) or VE-821 (ATR inhibitor) induced cell death when combined with FGF2. Sus-tained MAPK-ERK1/2 overactivation induced by FGF2 appears to under-lie these synthetic lethalities, as late pharmacological inhibition of thispathway restored cell homeostasis and prevented these described synergies.Our results highlight how mitotic signaling pathways which are frequentlyoverridden in malignant transformation might be exploited to disrupt therobustness of cancer cells, ultimately sensitizing them to stress-targeted ther-apies. This approach provides a new therapeutic rationale for human can-cers, with important implications for tumors still lacking effectivetreatment, and for those that frequently relapse after treatment with avail-able therapies.
Keywords
FGF2;  malignant phenotype;  MAPK-ERK1/2;  mitogenic signaling;  stress-targeted therapy;  synthetic lethality

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Dias MH, Fonseca CS, Zeidler JD, Costa LLMA, Silva MS, Lopes EC, et al. Fibroblast growth factor 2 lethally sensitizes cancer cells to stress-targeted therapeutic inhibitors. Mol Oncol. 2019 Dec;13(2):290-306. doi:10.1002/1878-0261.12402.
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